The regulation of endothelial cell survival and death is critical to vascular development and homeostatis and to processes associated with arteriosclerosis including vascular remodeling, atherogenesis, and plaque neovascularization. The proposed studies examine the molecular basis of endothelial cell survival and death, focusing on those proteins that support survival or oppose death. The underlying hypothesis of this proposal is that proteins of the Bcl-2 family determine endothelial cell survival under both basal conditions and during exposure to inflammatory and toxic stimuli. The specific aims proposed test several aspects of this hypothesis, examining the molecular basis and consequences of endothelial cell survival and apoptosis (programmed cell death) in vitro and in vivo models. The Specific Aims are: 1) to characterize the role of integrin- dependent adherence and signaling in the mechanisms of endothelial cell survival in vitro; 2) to characterize the signal transduction pathways mediated by TNF-alpha that induce the Bcl-2 homologue, A1 and that A1 inhibits; 3) to study the function of A1 in vivo by generating A1- deficient mice; and 4) to examine the mechanisms by which apoptotic endothelial cells become proadhesive for leukocytes. Insights gained from these studies may suggest new potential targets for the treatment of atherosclerosis and its complications.